Cancer is not a single entity but rather a highly individualized spectrum of diseases characterized by a number of genetic and genomic alterations (Hanahan and Weinberg, 2011). Distinguishing molecular alterations that constitute true drivers of cancer phenotypes from the multitude that are simply de-regulated has proven to be a daunting task, which is further exacerbated by the complexity of elucidating how such drivers interact synergistically to elicit cancer phenotypes. Prostate cancer is particularly challenging because its notorious heterogeneity, combined with a relative paucity of recurrent gene mutations, has made prostate cancer especially difficult to identify molecularly distinct subtypes with known clinical outcomes (Baca et al., 2013; Schoenborn et al., 2013; Shen and Abate-Shen, 2010). Additionally, while early-stage prostate tumors are readily treatable (Cooperberg et al., 2007), advanced prostate cancer frequently progresses to castration-resistant disease, which is often metastatic and nearly always fatal (Ryan and Tindall, 2011; Scher and Sawyers, 2005).
It should be noted that several factors, including an increase in the aging population and widespread screening for prostate specific antigen (PSA), have contributed to a substantial rise in diagnoses of prostate cancer. The primary means of determining the appropriate treatment course for men diagnosed with prostate cancer still relies on Gleason grading, a histopathological evaluation that lacks a precise molecular correlate. While patients with high Gleason score (Gleason ≥8) tumors are recommended to undergo immediate treatment, the appropriate treatment for those with low (Gleason 6) or intermediate (Gleason 7) Gleason score tumors remains more ambiguous. Indeed, although the majority of Gleason grade 6 tumors, as well as many Gleason grade 7 tumors, are likely to remain indolent (i.e., low-risk, non-aggressive or non-invasive), a minority (˜10%) will progress to aggressive disease.
Indeed, the current lack of reliable and reproducible assays to identify tumors destined to remain indolent versus those that are aggressive, has resulted in substantial overtreatment of patients that would not die of the disease if left untreated. Consequently, “active surveillance” has emerged as an alternative for monitoring men with indolent prostate cancer, with the goal of avoiding treatment unless there is evidence of disease progression. The obvious advantage of active surveillance is that it avoids overtreatment; however, the potential concern is that it may miss the opportunity for early intervention for patients with aggressive tumors. Therefore, better methods with a molecular correlate for diagnosing aggressive prostate cancer have great value.